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Biomedical subjects

E Cutz

Publications and source records attributed to E Cutz.

At least 37 records · Page 2Linked to original sources
PubMed2000

Cell death in human lung transplantation: apoptosis induction in human lungs during ischemia and after transplantation.

OBJECTIVE: To examine the presence and extent of apoptosis as well as the affected cell types in human lung tissue before, during, and after transplantation. SUMMARY BACKGROUND DATA: Apoptosis has been described in various human and animal models of ischemia-reperfusion injury, including heart, liver, and kidney, but not in lungs. Therefore, the presence of apoptosis and its role in human lungs after transplantation is not clear. METHODS: Lung tissue biopsies were obtained from 20 consecutive human lungs for transplantation after cold ischemic preservation (1-5 hours), after warm ischemia time (during implantation), and 30, 60, and 120 minutes after graft reperfusion. To detect and quantify apoptosis, fluorescent in situ end labeling of DNA fragments (TUNEL assay) was used. Electron microscopy was performed to verify the morphologic changes consistent with apoptosis and to identify the cell types, which were lost by apoptosis. RESULTS: Almost no evidence of apoptosis was found in specimens after immediate cold and warm ischemic periods. Significant increases in the numbers of cells undergoing apoptosis were observed after graft reperfusion in a time-dependent manner. The mean fraction of apoptotic cells at 30, 60, and 120 minutes after graft reperfusion were 16.6%, 22.1%, and 34.9% of total cells, respectively. Most of the apoptotic cells appeared to be alveolar type II pneumocytes, as confirmed by electron microscopy. CONCLUSIONS: Programmed cell death (apoptosis) appears to be a significant type of cell loss in human lungs after transplantation, and this may contribute to ischemia-reperfusion injury during the early phase of graft reperfusion. This cell loss might be responsible for severe organ dysfunction, which is seen in 20% of patients after lung transplantation. Therefore, this work is of importance to surgeons for the future development of interventions to prevent cell death in transplantation.

Adolescent↗
PubMed2000

Safety and efficiency of metered dose inhaler delivery of salbutamol in the intubated rabbit.

OBJECTIVE: To determine the safety and efficiency of metered dose inhaler salbutamol delivered to the intubated rabbit. DESIGN: Prospective, comparative, five-group laboratory investigation. SETTING: Animal laboratory, Department of Nuclear Medicine. SUBJECTS: A total of 30 adult, anesthetized New Zealand White rabbits. INTERVENTIONS: Three groups of rabbits underwent tracheal intubation through a tracheostomy and received 5 puffs of 99mTcO4 salbutamol delivered at the elbow connector (group 1) or via a catheter with its distal tip positioned at the midpoint (group 2) or bevel of the endotracheal tube (group 3). No intervention was provided for the rabbits in the fourth group. A fifth group underwent tracheal intubation through the mouth and received salbutamol (5 puffs) delivered at the bevel of the endotracheal tube. MEASUREMENTS: Delivery efficiency was expressed as the ratio of radioactivity emitted from lungs and trachea to the total radioactivity of the administered dose. Histopathologic injury scores were assigned to each trachea or lung specimen. MAIN RESULTS: Delivery efficiency was 30 times greater in groups 3 and 5 (full catheter) than in group 1 (elbow). The injury scores were similar in all groups. CONCLUSION: We conclude that the increased efficiency obtained by administration of metered dose inhaler salbutamol at the distal tip of endotracheal tube is not necessarily associated with increased epithelial injury.

Adrenergic beta-Agonists↗
PubMed2000

Gastric metaplasia: a frequently overlooked feature of duodenal biopsy specimens in untreated celiac disease.

BACKGROUND: Duodenal gastric metaplasia is rarely reported in untreated celiac disease, although it is seen in 60% to 100% of duodenal biopsy specimens in nonceliac patients with histologic duodenitis. The low incidence could represent underreporting, a decreased incidence in pediatric patients generally, or the more distal sampling site that is customary for most biopsy specimens that are obtained to diagnose celiac disease. It could also be a unique feature of the inflammatory reaction that characterizes this disease. The purpose of this study was to examine the incidence of gastric metaplasia in duodenal specimens from children with untreated celiac disease with special reference to patient age and biopsy site. METHOD: Formalin-fixed paraffin-embedded specimens of duodenal mucosa were selected from the pathology department's archival material. Sections were either stained histochemically or by immunochemical methods, according to an antigen-retrieval protocol. Forty-four duodenal specimens from untreated patients with celiac disease (n = 22) and control subjects of similar age with normal histology (n = 22) were examined. Ten of each were obtained during upper endoscopy from the proximal duodenum (proximal site) and 12 of each by Crosby capsule near the ligament of Treitz (distal site). RESULTS: All specimens from patients with celiac disease exhibited marked villous atrophy. None had been noted to have gastric metaplasia during routine examination of sections stained by hematoxylin and eosin. Fifteen (68%) of 22 of the celiac specimens and 2 of 22 (9%) control specimens contained gastric metaplasia, identified as patches of gastric-type cells containing MUC5AC (gastric mucin), pS2 (gastric trefoil factor) and neutral (periodic acid-Schiff-positive) mucin. Five of the seven celiac specimens that had no metaplasia showed increased numbers of goblet cells expressing gastric markers. The incidence of gastric metaplasia was not different for endoscopic (70%) or capsule (67%) specimens. Sixty-eight percent (7/11) of patients aged less than 3 years had gastric metaplasia. CONCLUSION: The presence of gastric metaplasia has been previously underreported in celiac disease specimens. Detection would be improved by the routine use of period acid-Schiff/ alcian blue staining. The incidence of gastric metaplasia in celiac disease is not significantly influenced by biopsy site or age at time of the biopsy.

Age Factors↗
PubMed2000

The pathogenesis of duodenal gastric metaplasia: the role of local goblet cell transformation.

BACKGROUND AND AIMS: Gastric metaplasia is frequently seen in biopsies of the duodenal cap, particularly when inflamed or ulcerated. In its initial manifestation small patches of gastric foveolar cells appear near the tip of a villus. These cells contain periodic acid-Schiff (PAS) positive neutral mucins in contrast with the alcian blue (AB) positive acidic mucins within duodenal goblet cells. Previous investigations have suggested that these PAS positive cells originate either in Brunner's gland ducts or at the base of duodenal crypts and migrate in distinct streams to the upper villus. To investigate the origin of gastric metaplasia in superficial patches, we used the PAS/AB stain to distinguish between neutral and acidic mucins and in addition specific antibodies to immunolocalise foveolar cell mucin MUC5AC, the foveolar cell secretory product, gastric trefoil factor (TFF1), the mature goblet cell mucin MUC2, and MUC2 core antigen. RESULTS: Cells in focal patches of gastric metaplasia contained secretory granules of both gastric and goblet cell phenotypes. MUC5AC and TFF1 were present as expected in gastric foveolar cells but in addition, MUC2 core antigen, normally present only in the Golgi of intestinal goblet cells, was expressed in secretory granules. Goblet cells in the vicinity of metaplastic patches also expressed both gastric and intestinal antigens. MUC5AC/MUC2 containing goblet cells were most common near the villus tip but were also seen at the base of crypts. Where crypts and Brunner's gland ducts merged they were always seen on the crypt side of the junction. Goblet cells were the only cells to express gastric antigens in these areas. In advanced metaplastic lesions, dual phenotype goblet cells were less evident and fewer cells expressed intestinal mucin antigens. CONCLUSIONS: We suggest that goblet cells that express both intestinal and gastric antigens may represent local precursors of gastric metaplasia undergoing a transition to foveolar-like cells of mixed phenotype at the site of early metaplastic patches. As metaplasia becomes more widespread, a more pure gastric phenotype emerges. This progression is likely to be controlled by local inflammatory signals.

Adolescent↗
PubMed2000

Deficiency of lamellar bodies in alveolar type II cells associated with fatal respiratory disease in a full-term infant.

We report a case of a full-term female infant who presented with severe respiratory distress shortly after birth and died at 23 d of age with unremitting respiratory failure. Infectious and other known causes of respiratory disease in this clinical setting were excluded. Examination of a lung biopsy showed abnormal lung parenchyma with features reminiscent of desquamative interstitial pneumonitis. Ultrastructural studies revealed that alveolar type II cells lacked cytoplasmic lamellar bodies, while other organelles appeared normal. Histochemical and immunohistochemical investigations indicated normal alveolar type II cell marker expression including surfactant proteins (SP-A, SP-B, pro-SP-B, and pro-SP-C). Mutations in the coding sequences of the SP-B gene were excluded as a cause of disease. This case appears to be a novel congenital defect affecting the pulmonary surfactant system. The cellular abnormality may involve the assembly of cytoplasmic lamellar bodies in alveolar type II cells-the principal storage site of pulmonary surfactant.

Biopsy↗
PubMed2000

Epithelial Na(+) channel (ENaC) expression in the developing normal and abnormal human perinatal lung.

Impaired lung epithelial Na(+) channel (ENaC) activity at the time of birth results in respiratory distress. To investigate potential mechanisms, the ontogeny and cellular distribution of the alphaENaC subunit mRNA expression was studied in normal, immature, and abnormal (hypoplastic) human fetal lungs using nonradioisotopic in situ hybridization. Surprisingly, alphaENaC expression was detected at the embryonic stage of normal lung development (4 to 5 wk gestation) when expression was localized to the fetal lung bud epithelium. By late gestation, ENaC was expressed in the conductive and respiratory airway epithelium, serous cells, and the distal lung unit in an alveolar type II (ATII) epitheliumlike distribution. Significant alphaENaC expression was found in newborn lung diseases associated with respiratory distress. One explanation is that alphaENaC mRNA is constitutively expressed, and that activity is regulated, at least in part, at the post-transcriptional level. Alternative explanations are that the expression of the beta or gammaENaC subunits may be impaired in certain newborn lung diseases or that alternate Na(+) permeant channels or transporters are important to lung liquid absorption in humans at birth.

Biological Transport, Active↗
PubMed1999

Neuroepithelial bodies as airway oxygen sensors.

Since the discovery of neuroepithelial bodies (NEB) in the late 1930s, evidence has accumulated to suggest that these cells may function as hypoxia-sensitive airway sensors. Until recently, this hypothesis was based largely on morphological observations. The use of in vitro models of isolated NEB, combined with electrophysiological approaches, have provided direct evidence that NEB cells express a membrane-bound O2 sensor and are the transducers of hypoxic stimulus. Here, we review the historical evidence and current state of knowledge of the oxygen-sensing properties of NEB cells, comparison with other O2 sensing cells, as well as recent advances that have been made using molecular and electrophysiological techniques. The possible role of NEB in perinatal pulmonary pathophysiology is also discussed.

Animals↗
PubMed1999

Selective modulation of membrane currents by hypoxia in intact airway chemoreceptors from neonatal rabbit.

1. We previously described voltage-dependent ionic currents and hypoxia chemosensitivity in cultured pulmonary neuroepithelial body (NEB) cells isolated from fetal rabbit. Here we use fresh neonatal rabbit lung slices (200-400 micrometer thick) to characterize the electrophysiological properties of 'intact' NEBs with patch-clamp, whole-cell recording. 2. Under voltage clamp, outward currents were partially inhibited by TEA (20 mM), 4-amino pyridine (4-AP; 2 mM) and cadmium (Cd2+; 100 micrometer), suggesting the presence of both Ca2+-dependent (IK(Ca)) and Ca2+-independent (IK(V)) components. 3. Inward currents, carried by voltage-dependent Ca2+ channels and also, in occasional cells (approximately 11%), by TTX-sensitive Na+ channels, were also detected in intact NEB cells. 4. Hypoxia (PO2 = 15-20 mmHg) reduced the outward K+ current by approximately 34% during voltage steps from -60 to +30 mV, while inward Ca2+ or Na+ currents were not affected by hypoxia. Hypoxia suppressed roughly equally both IK(Ca) and IK(V) components of outward current, and no further inhibition of K+ currents was seen with either TEA and 4-AP + hypoxia. 5. Diphenylene iodonium (DPI; 1 microM) suppressed outward K+ current by approximately 42%, and DPI + hypoxia had no additional effect on the K+ current. 6. Direct application of H2O2 augmented outward K+ current; for a voltage step from -60 mV to +30 mV, 0.25 mM H2O2 increased K+ current by approximately 37%. 7. These results indicate that intact neonatal NEB cells express hypoxic chemosensitivity and introduce the rabbit lung slice preparation as an new model for investigating the role of airway O2 chemoreceptors.

4-Aminopyridine↗
PubMed1999

Pulmonary barotrauma in congenital diaphragmatic hernia: a clinicopathological correlation.

BACKGROUND/PURPOSE: The high mortality rate in congenital diaphragmatic hernia (CDH) has been ascribed to pulmonary hypoplasia and persistent pulmonary hypertension of the newborn (PPHN). One of the principal treatment strategies has been the use of hyperventilation to reverse ductal shunting, but the wisdom of this approach is being questioned because of parenchymal lung injury from high inflation pressures. The authors hypothesize that the use of hyperventilation to reverse or prevent ductal shunting would result in ventilator-induced lung injury, which would be evident on postmortem examination. A retrospective review of clinical and autopsy information was conducted. METHODS: Clinical and autopsy information gathered for a previously published series of 223 infants with CDH presenting in the first 24 hours of life was reviewed. Autopsy and clinical data were analyzed from 68 of 101 nonsurvivors who died with severe hypoxemia. RESULTS: Sixty-two of 68 cases (91%) had evidence of diffuse alveolar damage and hyaline membrane formation, which was more evident in the ipsilateral lung. Forty-four (65%) infants had pneumothoraces, and 4 infants had interstitial fibrosis. Pulmonary hemorrhage was seen in 35 cases (50 maximum peak inspiratory pressure [mean +/- SD] was 40.4+/-7.9 cm H2O and lowest modified ventilatory index [respiratory rate x peak airway pressure] was 2323+/-836). The degree of pulmonary hypoplasia was evaluated by lung weight with the ratio of the observed combined lung weight to the expected lung weight based on birth weight and gestational age. The ratio based on birth weight was 57%+/-25%, and the ratio based on gestational age was 60%+/-26%. Twenty-one infants (35%) had nonpulmonary anomalies. The most significant was a 10% incidence of congenital heart disease. Apart from this, lethal nonpulmonary anomalies were rare. CONCLUSION: These results suggest that lung injury secondary to mechanical ventilation plays an important role in the mortality rate of patients with CDH, which may become increasingly significant when there is underlying pulmonary hypoplasia.

Barotrauma↗
PubMed1999

Expression of serotonin receptor 2c in rat type II pneumocytes.

Serotonin (5-hydroxytryptamine [5-HT]) is a multifunctional amine with wide occurrence in both neural and non-neural tissues, including the lung. The diverse responses to 5-HT are elicited through activation of different 5-HT receptor subtypes. We report the expression and localization of 5-HT receptor 2c subtype (5-HT2c-R) in rat lungs using reverse transcriptase-polymerase chain reaction, nonisotopic in situ hybridization (NISH), and immunohistochemistry. At the messenger RNA (mRNA) level, signal corresponding to approximately 430 base pairs was detected in whole-lung tissue extracts as well as in cultures of isolated alveolar type II cells from fetal and adult rat lung. Using antisense RNA probe for 5-HT2c-R, NISH showed strong positive signal in type II cells. The expression of mRNA signal differed between fetal and adult rat type II cells, with weak, predominantly perinuclear localization in the former and strong cytoplasmic localization in the latter. Immunohistochemistry, using specific monoclonal antibody against 5-HT2c-R, showed perinuclear localization in fetal type II cells; whereas in adult type II cells 5-HT2c-R immunoreactivity was confined mostly to the plasma membrane, as demonstrated by laser confocal microscopy. Identification of 5-HT2c-R expression in alveolar type II cells suggests an important role for this amine in modulating the function of these cells. The differences in cell domain localization between fetal and adult type II cells could indicate developmental regulation of 5-HT2c-R expression in the lung.

Animals↗
PubMed1998

Assessment of the efficacy of in vivo CFTR protein replacement therapy in CF mice.

Cystic Fibrosis (CF) is caused by mutations in the CF gene that lead, for the most part, to mislocalization of the protein product, the cystic fibrosis transmembrane conductance regulatory (CFTR). CFTR is a chloride channel normally situated in the apical membrane of epithelial cells where it contributes to transepithelial ion transport. In this study we demonstrated the feasibility of in vivo transfer of purified CFTR protein via phospholipid liposomes into the apical membrane of nasal epithelia of CFTR knockout mice. Membrane incorporation of immunogold-labeled CFTR could be visualized by electron microscopy and correction of CF-related defects in ion transport measured by nasal potential difference (PD) measurements in about one-third of the animals treated. Although these initial results are promising, effectiveness of this therapeutic approach appears to be limited by the inefficient incorporation of CFTR into the apical epithelial cell membrane.

Amiloride↗
PubMed1998

Neonatal adrenal congestion: a sonographic-pathologic correlation.

We reviewed the clinical, sonographic and pathologic findings in eight neonates in whom diffuse enlargement and abnormal echogenicity of the adrenal glands was documented sonographically. Four of the patients suffered from perinatal asphyxia and two others required mechanical ventilation for other reasons. Six patients died and one suffers from severe development delay, cerebral palsy and failure to thrive. Sonographically, the glands were enlarged, their surface was smooth and there was loss of the central echogenic stripe. Diffuse sinusoidal congestion was found histologically in all five in whom autopsies were performed. These sonographic findings represent part of the spectrum of adrenal changes in neonatal asphyxia and other causes of perinatal stress, and may be associated with poor outcome because of other sequelae of asphyxia.

Adrenal Glands↗
PubMed1998

Autopsy in a neonatal intensive care unit: utilization patterns and associations of clinicopathologic discordances.

OBJECTIVES: (1) To develop methods to describe autopsy utilization patterns in a neonatal intensive care unit. (2) To identify classes of patients likely to have clinicopathologic concordance or discordance. METHODS: Five hundred forty-five consecutive neonatal intensive care unit deaths (338 autopsied, rate 62%) in a regional tertiary/quaternary care neonatal intensive care unit for referred infants (65,000 annual births) were classified in six clinical diagnostic groups (anomalies, cardiac anomalies, hypoxic ischemic encephalopathy, prematurity and its complications, infections, and other) and rated in three levels of certainty of clinical diagnosis as "gold standard" certainty, almost complete certainty, and less certain than the latter. Clinicopathologic discordances were rated in three classes using clinical, pathologic, and multidisciplinary mortality conference records. The proportions of autopsied cases, cases with major discordances, and cases with no discordances were compared and analyzed in relation to diagnostic group and level of certainty. RESULTS: Performance of autopsy was associated with clinical diagnostic uncertainty (p = 0.008). Major discordances with implications for outcome (Class I) were found in 3%, and without implications for outcome (Class II) in 15% of cases; 42% of cases had no discordances. Major discordance rate varied inversely with the degree of diagnostic certainty (p = 0.000) and varied among clinical groups. CONCLUSIONS: (1) Autopsy was used most for cases with potential for high yields. (2) Clinicopathologic discordances were more frequent and important in certain clinical diagnostic groups (prematurity, other) and with high levels of diagnostic uncertainty. When the diagnostic "gold standard" is available during life, autopsy will provide little information.

Autopsy↗
PubMed1998

Rapid reperfusion causes stress failure in ischemic rat lungs.

OBJECTIVE: Rapid reperfusion may be injurious to the ischemic lung. Our aim was to confirm that slow reperfusion improves postischemic pulmonary function and to elucidate the ultrastructural changes associated with slow versus rapid reperfusion. METHODS. We used an ex vivo perfused rat lung transplant model to study the effect of slow versus rapid reperfusion on subsequent lung function and morphologic conditional. Functional assessment was performed in (1) fresh lung, slowly reperfused; (2) fresh lung, rapidly reperfused; (3) ischemic lung (4 hours at 22 degrees C), slowly reperfused; and (4) ischemic lung, rapidly reperfused. RESULTS: In group 4, the shunt fraction (P=.001), airway pressure (P=.001), and wet/dry ratio (P=.01) were significantly higher than in groups 1 through 3. Light and electron microscopy of slowly reperfused ischemic lungs (n=4) appeared normal. Rapidly reperfused ischemic lungs (n=4) demonstrated massive alveolar edema hemorrhage, and epithelial "blebbing" by light microscopy. Electron microscopy identified the blebbing as separation of the epithelial layer from an intact basement membrane by edema fluid. The epithelial layer was disrupted in numerous locations. Complete disruption of all layers of the blood-gas barrier was occasionally present. CONCLUSION: Rapid reperfusion of the ischemic lung is an important contributing factor to reperfusion lung injury resulting in mechanical stress failure of the alveolar/capillary barrier. Gradual reintroduction of blood flow to the ischemic lung improves oxygenation.

Animals↗
PubMed1998

Attenuation of ventilator-induced acute lung injury in an animal model by inhibition of neutrophil adhesion by leumedins (NPC 15669).

OBJECTIVES: Beta2-integrin (CD11b/CD18) expression, an indicator of neutrophil activation, has been associated with the development of acute respiratory distress syndrome. Leumedins act directly on leukocytes to inhibit the up-regulated expression of beta2-integrins involved in leukocyte adhesion. We examined the effect of such a new anti-inflammatory agent, NPC 15669 (N-[9H-(2,7-dimethylfluorenyl-9-methoxy)-carbonyl]-L-leucine), on neutrophil-mediated acute lung injury in an animal model. DESIGN: Prospective, randomized, blinded, controlled animal study. SETTING: An animal laboratory in a university setting. SUBJECTS: Adult New Zealand rabbits. INTERVENTIONS: After repeated lung lavages with normal saline to induce acute lung injury, anesthetized rabbits were randomly assigned to one of two groups (n = 6 per group): a) treatment group (pretreated with NPC 15669 [10 mg/kg i.v. bolus] 30 mins before lavage, followed by a continuous infusion [5 mg/kg/hr] for the duration [4 hrs] of the experiment); or b) control group (pretreatment and continuous infusion with placebo). All animals were mechanically ventilated with identical pressure settings over 4 hrs and were killed at the end of the experiment. MEASUREMENTS AND MAIN RESULTS: PaO2, PaCO2, and tidal volumes were repeatedly measured and airway pressure settings were noted every 30 mins. At the end of the experiment, lungs were taken out for measurements of the myeloperoxidase content, for conventional histology (hematoxylin and eosin staining), and for intracellular adhesion molecule-1 immunohistostaining. Pretreatment with NPC 15669 profoundly improved oxygenation from a PaO2 of 52 +/- 5 torr (6.9 +/- 0.7 kPa) to 250 +/- 161 torr (33.3 +/- 21.5 kPa) within 60 mins after lung lavage (p < .05). Oxygenation continued to improve throughout the study, reaching a maximal PaO2 value of 395 +/- 98 torr (52.7 +/- 13.1 kPa) at 4 hrs. In the control group, oxygenation remained poor throughout the observation period. PaO2 values differed significantly (51 +/- 20 torr [6.8 +/- 2.7 kPa] vs. 306 +/- 126 torr [40.8 +/- 16.8 kPa], p < .005) at 90 mins and at all subsequent measurements from those values in the NPC 15669 group. Dynamic lung compliance improved significantly 60 to 90 mins after repeated lung lavage. Histology demonstrated markedly less lung damage (hyaline membrane formation and leukocyte infiltration) in treated animals (p < .05) than in controls. CONCLUSIONS: NPC 15669 seems to block inflammatory reactions by inhibiting the sequestration of neutrophils in acute, ventilator-associated lung injury. As a result, gas exchange and total lung compliance improve. Application of this and similar compounds affecting neutrophil adhesion warrants further investigation as a treatment modality for acute lung injury.

Animals↗